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Int. J. Mol. Sci. 2015, 16(1), 1980-2000; doi:10.3390/ijms16011980

Medullary Thymic Epithelial Cells and Central Tolerance in Autoimmune Hepatitis Development: Novel Perspective from a New Mouse Model

Department of Medicine and Clinical Immunology, the Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1089, New York, NY 10029, USA
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Author to whom correspondence should be addressed.
Academic Editor: Johannes Haybaeck
Received: 10 December 2014 / Accepted: 7 January 2015 / Published: 16 January 2015
(This article belongs to the Collection Molecular Mechanisms of Human Liver Diseases)
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Abstract

Autoimmune hepatitis (AIH) is an immune-mediated disorder that affects the liver parenchyma. Diagnosis usually occurs at the later stages of the disease, complicating efforts towards understanding the causes of disease development. While animal models are useful for studying the etiology of autoimmune disorders, most of the existing animal models of AIH do not recapitulate the chronic course of the human condition. In addition, approaches to mimic AIH-associated liver inflammation have instead led to liver tolerance, consistent with the high tolerogenic capacity of the liver. Recently, we described a new mouse model that exhibited spontaneous and chronic liver inflammation that recapitulated the known histopathological and immunological parameters of AIH. The approach involved liver-extrinsic genetic engineering that interfered with the induction of T-cell tolerance in the thymus, the very process thought to inhibit AIH induction by liver-specific expression of exogenous antigens. The mutation led to depletion of specialized thymic epithelial cells that present self-antigens and eliminate autoreactive T-cells before they exit the thymus. Based on our findings, which are summarized below, we believe that this mouse model represents a relevant experimental tool towards elucidating the cellular and molecular aspects of AIH development and developing novel therapeutic strategies for treating this disease. View Full-Text
Keywords: autoimmune hepatitis (AIH); T-cells; medullary thymic epithelial cells; medullary thymic epithelial cells (mTECs); central tolerance; peripheral tolerance; autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED); autoimmune polyendocrine syndrome (APS); regulatory T-cells; soluble liver antigen; antinuclear antibodies autoimmune hepatitis (AIH); T-cells; medullary thymic epithelial cells; medullary thymic epithelial cells (mTECs); central tolerance; peripheral tolerance; autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED); autoimmune polyendocrine syndrome (APS); regulatory T-cells; soluble liver antigen; antinuclear antibodies
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Alexandropoulos, K.; Bonito, A.J.; Weinstein, E.G.; Herbin, O. Medullary Thymic Epithelial Cells and Central Tolerance in Autoimmune Hepatitis Development: Novel Perspective from a New Mouse Model. Int. J. Mol. Sci. 2015, 16, 1980-2000.

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